Lipid bilayer position and orientation of novel carprofens, modulators of γ-secretase in Alzheimer's disease.

γ-Secretase is an integral membrane protein complex and is involved in the cleavage of the amyloid precursor protein APP to produce amyloid-β peptides. Amyloid-β peptides are considered causative agents for Alzheimer's disease and drugs targeted at γ-secretase are investigated as therapeutic treatments. We synthesized new carprofen derivatives, which showed γ-secretase modulating activity and determined their precise position, orientation, and dynamics in lipid membranes by combining neutron diffraction, solid-state NMR spectroscopy, and molecular dynamics simulations.

Structural Characterization of the Amyloid Precursor Protein Transmembrane Domain and Its γ-Cleavage Site.

Alzheimer's disease is the most common form of dementia that affects about 50 million of sufferers worldwide. A major role for the initiation and progression of Alzheimer's disease has been associated with the amyloid β-peptide (Aβ), which is a protease cleavage product of the amyloid precursor protein. The amyloid precursor protein is an integral membrane protein with a single transmembrane domain.

Calcium ions promote formation of amyloid β-peptide (1-40) oligomers causally implicated in neuronal toxicity of Alzheimer's disease.

Amyloid β-peptide (Aβ) is directly linked to Alzheimer's disease (AD). In its monomeric form, Aβ aggregates to produce fibrils and a range of oligomers, the latter being the most neurotoxic. Dysregulation of Ca(2+) homeostasis in aging brains and in neurodegenerative disorders plays a crucial role in numerous processes and contributes to cell dysfunction and death.

Brain tissue oxygen and outcome after severe traumatic brain injury: a systematic review.

Objective: In this study, available medical literature were reviewed to determine whether brain hypoxia as measured by brain tissue oxygen (Bto2) levels is associated with increased risk of poor outcome after traumatic brain injury (TBI). A secondary objective was to examine the safety profile of a direct BtO2 probe. DATA SOURCE AND EXTRACTION: Clinical studies published between 1993 and 2008 were identified from electronic databases, Index Medicus, bibliographies of pertinent articles, and expert consultation.

Using fluorescence correlation spectroscopy to study conformational changes in denatured proteins.

Fluorescence correlation spectroscopy (FCS) is a sensitive analytical tool that allows dynamics and hydrodynamics of biomolecules to be studied under a broad range of experimental conditions. One application of FCS of current interest is the determination of the size of protein molecules in the various states they sample along their folding reaction coordinate, which can be accessed through the measurement of diffusion coefficients. It has been pointed out that the analysis of FCS curves is prone to artifacts that may lead to erroneous size determination.

Expression and purification of active PKB kinase from Escherichia coli.

PKB/Akt is a protein involved in control of apoptosis, proliferation and cellular metabolism, and it has been found to be activated in many cancers. Activation of PKB involves recruitment of the enzyme by its PH domain to the cell membrane, and phosphorylation at two residues, T308 and S473. To produce active PKB kinase from Escherichia coli, we constructed a derivative of PKB lacking the PH domain and mutated to glutamate at residues S124, T450 and the activating residue S473 (DeltaPH-PKB-EEE).

delta-Aminolevulinic acid and blue light photodynamic therapy for treatment of multiple basal cell carcinomas in two patients with nevoid basal cell carcinoma syndrome.

Background: Patients with nevoid basal cell carcinoma syndrome suffer from multiple basal cell carcinomas, requiring numerous surgical procedures that over time leave them with multiple disfiguring scars. Photodynamic therapy with delta-aminolevulinic acid using red light (approximately 630 nm) sources has been reported as effective in treatment of superficial and small nodular basal cell carcinomas. To our knowledge, the blue light source (417 nm peak irradiance) approved by the FDA for treatment of actinic keratoses has not been used for photodynamic therapy with delta-aminolevulinic acid of basal cell carcinoma.

Nucleotide exchange from the high-affinity ATP-binding site in SecA is the rate-limiting step in the ATPase cycle of the soluble enzyme and occurs through a specialized conformational state.

We have characterized the kinetic and thermodynamic consequences of adenine nucleotide interaction with the low-affinity and high-affinity nucleotide-binding sites in free SecA. ATP binds to the hydrolytically active high-affinity site approximately 3-fold more slowly than ADP when SecA is in its conformational ground state, suggesting that ATP binding probably occurs when the enzyme is in another conformational state during the productive ATPase/transport cycle. The steady-state ATP hydrolysis rate is equivalent to the rate of ADP release from the high-affinity site under a number of conditions, indicating that this process is the rate-limiting step in the ATPase cycle of the free enzyme.

Phospholipid-induced monomerization and signal-peptide-induced oligomerization of SecA.

The SecA ATPase drives the processive translocation of the N terminus of secreted proteins through the cytoplasmic membrane in eubacteria via cycles of binding and release from the SecYEG translocon coupled to ATP turnover. SecA forms a physiological dimer with a dissociation constant that has previously been shown to vary with temperature and ionic strength. We now present data showing that the oligomeric state of SecA in solution is altered by ligands that it interacts with during protein translocation.

[Experience in using systems for automating endoscopic diagnosis].

The specific features of processes of current methods for instrumental diagnosis, which are used at therapeutical-and-prophylactic institutions are considered. Main problems in automation of endoscopic diagnosis and the current methods of their solution are discussed. Tasks required to put an automatic diagnostic system into practice are defined.

Vrms/T quantitation: usefulness in patients with neuropathies.

This study evaluates the sensitivity of root mean square voltage (Vrms)/turns (T) ratios in neuropathies. Data were recorded with concentric needle electrodes from the biceps brachii, first dorsal interosseous, tibialis anterior, and calf muscles. Recordings were analyzed from 35 normal subjects as well as 24 consecutive patients referred for evaluation of neuropathic disorders.

Gaucher's disease: case report of mandibular trauma.

Gaucher's disease is a disturbance of lipid storage that results in the accumulation of histiocytes filled with glucosyl ceramide in various organs and bones. Clinical features include history of epistaxis, hemoptysis, and spontaneous gingival hemorrhage. This article reviews Gaucher's disease with reference to its importance to dental practitioners and a case involving mandibular trauma is presented.

Progressive osseous destruction as a complication of HIV-periodontitis.

A pathologic condition is described, characterized by rampant necrosis of gingival mucosa, periodontium, and related osseous structures associated with systemic infection with the human immunodeficiency virus (HIV). It is believed that this condition is an extension beyond the normal clinical course of HIV-periodontitis (HIV-P) and manifests itself in three progressive stages: (1) HIV-associated gingivitis, (2) HIV-P, and (3) an extension of HIV-P to osseous necrosis. Two cases of osseous destruction attending HIV-P are reported, one of which led to initial diagnosis of HIV infection.

Use of a prefabricated splint for segmental augmentation of the mandibular alveolar ridge with hydroxyapatite.

Hydroxyapatite is a biocompatible material for augmentation of edentulous ridges to improve patient comfort and denture stability. The problems associated with hydroxyapatite are generally related to the amount of material introduced and the site of implantation. This article describes the use of a prefabricated splint that permits localization of the implant material to selected sites of the mandible and restricts the amount of material used.

Posterior segmental osteotomy with simultaneous endosseous implant placement to facilitate fixed reconstruction.

The supra-eruption of the edentulous posterior maxilla may decrease interarch space, thus compromising the construction of an adequate fixed or removable prosthetic appliance (Henderson et al., 1985). The following case report illustrates a treatment which provides additional interarch space facilitating the restoration of the patient's dentition with a fixed prosthetic appliance.